Loss of GABAergic interneurons is a major feature of temporal lobe epilepsy, both in human patients as well as animal models. The aim of the proposed research is to determine whether selective, focal interneuron lesions result in interictal spikes and seizures. This research will test the hypothesis that interneuron loss, independent of other local-circuit mechanisms, contributes significantly to the generation of epileptic seizures. The proposed studies will utilize a neurotoxin approach, as well as an independent genetic technique, to selectively ablate interneurons. The two approaches will initially lesion heterogeneous populations of interneurons, but subsequent studies will focus on specific sub-types of interneurons. The interneuron ablations will be followed by continuous in vivo video-LFP monitoring and in vitro assessment of the electrophysiological properties of the remaining principal cells and their networks. The results of these experiments will improve our understanding of the role that the loss of GABAergic interneurons plays in seizure generation and epileptogenesis. PUBLIC HEALTH RELEVANCE: In temporal lobe epilepsy, people become susceptible to seizures, which disrupt their daily lives. This disease affects millions of people by changing the way different parts of their brain communicate. This research will shed light onto the biological mechanisms that lead to this disease. Specifically, we will study how selective removal of a small sub-population of inhibitory nerve cells from the brain contributes to the generation of seizures in the epileptic brain.